1. Field
The present invention relates to a therapeutic agent, and for example to a therapeutic composition of infectious or inflammatory diseases including peptide ligand that bonds with CXCR2 as an active component.
2. Description of Related Art
Infectious diseases include infections by viruses, bacteria, parasites, etc., and among these, bacterial infection diseases have been treated by antibiotics, but the recent abuse of antibiotics have created various super bacteria, and thus, seeking new treatment strategies on bacterial infection diseases are necessary. Inflammatory diseases are associated with failure in controlling immune response, which includes atopic dermatitis, asthma, arthritis, etc. These diseases are showing rapid increase regardless of age or sex which requires effective treatment with few side effects.
Sepsis is a complicated clinical syndrome that is general in intensive care unit, which is caused by host response that is harmful for infection and causes damage. It has been reported that more than 200,000 people died from sepsis in the United States. Moreover, severe sepsis and septic hack have remarkably increased over the past two decades. Since the death rate of severe sepsis and septic shock is high, developing a novel effective therapeutic agent for sepsis is desperate.
Death rate due to sepsis is associated with the failure in controlling inflammatory response, and this failure is caused by critical defect in the innate immune system. Excessive apoptosis of lymphocytes appears in sepsis, which results in paralysis of various organs. In an initial stage of sepsis, some pro-inflammatory cytokine including TNF-a and IL-1B remarkably increases and causes overall defunctionalization on host immune system. Furthermore, it has been known that aggressive bacteria plays a main role in the progress and the outbreak of sepsis. Therefore, it is appropriate to focus on developing an effective method on controlling bacteria by promoting activities of phagocytes, suppressing production of pro-inflammatory cytokines, and blocking apoptosis of immune cells.
CXCR2 is a receptor for a typical chemoattractant that is found in phagocytes such as neutrophils, monocytes and macrophages. In human beings, CXCL8 bonds to CXCR2. Although mouse homologue of CXCL8 does not exist, its function can be replaced with other chemokines from mouse that include CXCL1. In vitro activation of CXCR2 by CXCL8 or KC induces leukocyte chemotactic movement in neutrophils and monocytes. It has been discovered that expression of not CXCR1 but CXCR2 is controlled downward by 50% compared to normal control in a neutrophils of a sepsis patient. The down-regulation of CXCR2 leads to a failure of neutrophil activation caused by a CXCR2 ligand. There is a report that injection of a CXCR2 blocking antibody increases the survival rate in a sepsis experimental model. Moreover, the deficit of CXCR2 was reported to increase the survival rate. Exposure of CXCL8 causes defuntionalization of endothelial cells and collapse in normal anticoagulation of endothelia. Kuliopulos et al. demonstrated that administration of a novel pepducin (x1/2pal-3: pal-RTLFKAHMGQKHR (SEQ ID NO: 1)) ligand derived from an intracellular region of CXCR2 results in a remarkable increase in survival rate of cecal ligation and puncture (CLP)-septic mice by blocking a CXCR2-mediated signaling pathway by means of CXCL8 or CXCL1.